The overall goal of this proposal is to identify specific classes of nociceptors that contribute to two major types of pain, inflammatory pain and nerve injury pain. Furthermore, we aim to identify functional changes that occur in these classes of nociceptors. These studies will direct the development of novel pain therapies that target specific neural mechanisms on select populations of nociceptors. Two classes of unmyelinated nociceptors, which differ neurochemically and anatomically, have recently been identified. One class finds the plant isolectin B4 whereas the other class does not bind isolectin B4 but contains neuropeptides and expresses receptors for nerve growth factor. We have substantial preliminary data that show that these two classes of nociceptors are functionally distinct. Isolectin B4 positive and negative nociceptors have different action potential characteristics, different densities of Na+ channels and exhibit distinct responses to noxious heat (Stucky and Lewin, 1999). A prominent hypothesis in the literature is that isolectin B4 negative nociceptors mediate inflammatory pain whereas isolectin B4 positive nociceptors mediate nerve injury pain. However, this hypothesis has not been tested. Our goal is to use electrophysiological techniques to determine whether functional changes occur selectively in isolectin B4 positive or isolectin B4 negative nociceptors during nerve injury or inflammation. Furthermore, we will determine whether selective elimination of isolectin B4 positive or isolectin B4 negative nociceptors reduces or eliminates the behavioral hyperalgesia that occurs with nerve injury or inflammation.